Targeting the Pathobiology of Diabetic Kidney Disease

The pathobiology of diabetic kidney disease (DKD) involves an interplay between all the many different cell types that exist within the kidney and their shared and cumulative dysfunction in response to chronic hyperglycemia. DKD is characteriszed by morphological changes including tubular hypertrophy, podocyte dysfunction, mesangial expansion and mesangiolysis, endothelitis and capillary rarefaction, arteriolar hyalinosis, basement membrane thickening, and ultimately nephron dropout and tubulointerstitial fibrosis. These adaptive but ultimately maladaptive changes accelerate the progression of lesions in the diabetic kidney by increasing mechanical and oxidative stress, hypoxia, fibrogenesis, inflammation, senescence, and apoptosis. In particular, atrophy at the critical junction between Bowman's capsule and the proximal tubule likely represent the leading cause of nephron dropout and kidney function decline in DKD. Preventing, slowing, or reversing these changes should be the target of future “smart” therapies for patients with DKD, many of which are now under development. The pathobiology of diabetic kidney disease (DKD) involves an interplay between all the many different cell types that exist within the kidney and their shared and cumulative dysfunction in response to chronic hyperglycemia. DKD is characteriszed by morphological changes including tubular hypertrophy, podocyte dysfunction, mesangial expansion and mesangiolysis, endothelitis and capillary rarefaction, arteriolar hyalinosis, basement membrane thickening, and ultimately nephron dropout and tubulointerstitial fibrosis. These adaptive but ultimately maladaptive changes accelerate the progression of lesions in the diabetic kidney by increasing mechanical and oxidative stress, hypoxia, fibrogenesis, inflammation, senescence, and apoptosis. In particular, atrophy at the critical junction between Bowman's capsule and the proximal tubule likely represent the leading cause of nephron dropout and kidney function decline in DKD. Preventing, slowing, or reversing these changes should be the target of future “smart” therapies for patients with DKD, many of which are now under development. Clinical Summary•There remains an urgent need for new therapies that directly target the pathophysiologic pathways that lead the development and progression of diabetic kidney disease.•Rapidly improving understanding of the mechanisms underlying diabetic kidney disease will lead to new targets and smarter interventions to prevent or slow kidney damage. •There remains an urgent need for new therapies that directly target the pathophysiologic pathways that lead the development and progression of diabetic kidney disease.•Rapidly improving understanding of the mechanisms underlying diabetic kidney disease will lead to new targets and smarter interventions to prevent or slow kidney damage. Diabetic kidney disease (DKD) has been traditionally viewed as an organ-specific manifestation of “microvascular disease,” clustered with retinopathy and neuropathy and separate from atherogenic macrovascular disease leading to accelerated coronary heart disease, peripheral vascular disease, and cerebrovascular disease in people with diabetes. However, research over the last thirty years has demonstrated that the pathogenesis of DKD is far more complicated; involving an interplay between all the many different cell types that exist within the kidney and their shared and cumulative dysfunction in response to chronic hyperglycemia. In addition, in certain patients and populations, many comorbid factors modulate and often accelerate this process—including hypertension, dyslipidemia, obesity, intrarenal vascular disease, endothelial dysfunction, acute kidney injury, kidney ischemia, developmental nephron endowment, and acquired nephron loss. Together, these comorbidities make it clinically impossible to separate DKD from other forms of renal dysfunction in most people with diabetes and CKD or even to establish any specific activity of therapies against DKD in clinical trials. Indeed, the rapid responses seen in recent clinical trials with sodium glucose cotransporter 2 (SGLT2) inhibitors, including in individuals both with and without diabetes, suggest that the observed renoprotective benefits are probably not owing to specific actions on DKD.1Thomas M.C. Cherney D.Z.I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.Diabetologia. 2018; 61: 2098-2107Crossref PubMed Scopus (173) Google Scholar There are also clear benefits of renin angiotensin aldosterone system (RAAS) inhibition on the progression of kidney disease in patients with diabetes, despite an apparent lack of effect on early ultrastructural changes observed in the RAAS trial.2Katavetin P. Katavetin P. Renal and retinal effects of enalapril and losartan in type 1 diabetes.N Engl J Med. 2009; 361 (author reply 1411): 1410-1411Crossref PubMed Scopus (9) Google Scholar Such an argument is probably moot in the clinical setting, where renoprotection, however it is achieved, is vitally important. However, a directed therapy that will definitively prevent, slow, or reverse the characteristic changes in kidney structure and function known as “diabetic nephropathy” remains to be defined. This review will explore the recognized structural and functional changes observed in the diabetic kidney, the current understanding of their pathogenesis and their potential as treatment targets in DKD. Elevated plasma glucose levels in diabetes trigger increased GLUT1/2-dependent basolateral uptake of glucose that rapidly results in epithelial cell remodeling and (mal)adaptive tubular hypertrophy leading to an increase in total kidney mass.3Vallon V. Thomson S.C. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.Diabetologia. 2017; 60: 215-225Crossref PubMed Scopus (351) Google Scholar The induction of many different trophic factors is involved including epidermal growth factor, platelet-derived growth factor, hepatocyte-derived growth factor, fibroblast-derived growth factor, parathyroid hormone–related protein, vascular endothelial growth factor, transforming growth factor beta, insulin-like growth factor-1, and angiotensin II.4Thomas M.C. Brownlee M. Susztak K. et al.Diabetic kidney disease.Nat Rev Dis Primers. 2015; 1: 15018Crossref PubMed Scopus (401) Google Scholar These signals collectively push tubular cells into the growth phase of the cell cycle, followed by their arrest at the G1/S interface, locking them into a hypertrophic but ultimately dysfunctional (proinflammatory, profibrotic, senescent) phenotype. Although kidney hypertrophy increases resorption capacity, enhanced SGLT-mediated sodium flux in hypertrophied diabetic kidney also activates tubuloglomerular feedback pathways that increase glomerular capillary pressure and single-nephron glomerular filtration rate (GFR) (known as “hyperfiltration”). It is likely that tubular hypertrophy drives hyperfiltration, as diabetes-associated hyperfiltration is attenuated when kidney hypertrophy is also prevented (eg, ornithine decarboxylase inhibition5Thomson S.C. Deng A. Bao D. Satriano J. Blantz R.C. Vallon V. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes.J Clin Invest. 2001; 107: 217-224Crossref PubMed Scopus (204) Google Scholar). This appears to be mediated by enhanced SGLT2-mediated sodium reabsorption, as hyperglycemia is not followed by hyperfiltration in streptozotocin-treated SGLT2-deficient mice, despite the development of tubular hypertrophy in this model.6Vallon V. Thomson S.C. The tubular hypothesis of nephron filtration and diabetic kidney disease.Nat Rev Nephrol. 2020; 16: 317-336Crossref PubMed Scopus (160) Google Scholar Equally, hyperfiltration is prevented after SGLT2 inhibition, as increased delivery of sodium to the macula densa triggers a fall in transglomerular pressure and single-nephron GFR.1Thomas M.C. Cherney D.Z.I. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.Diabetologia. 2018; 61: 2098-2107Crossref PubMed Scopus (173) Google Scholar In advanced DKD, compensatory hyperfiltration is also observed, as nephron dropout and additional sodium flux in residual functioning nephrons strives to maintain sodium balance, again making SGLT2 inhibition a logical intervention in this setting. Diffuse thickening of the tubular basement membrane (TBM) and widening of the interstitial spaces with extracellular matrix is another important early change in diabetes, driven by fibrogenic changes in the “stressed” overlying proximal tubular cells that generate and maintain the TBM. Encapsulation by the thickened TBM further exacerbates mechanical pressures in the proximal tubule. At the same time, the progressive matrix expansion between peritubular capillaries, combined with increased energy demands of solute reabsorption with hypertrophy and hyperfiltration, increasing inefficiencies in mitochondrial ATP generation, changes in tubular blood flow and capillary rarefaction also act to increase hypoxic stress in the proximal tubule (Fig 1). Hypoxia and hypoxic adaptations are now recognized as a critical mediator of functional and structural change in the diabetic kidney, in particular, the proximal tubule.7Gilbert R.E. Proximal Tubulopathy: Prime Mover and key therapeutic target in diabetic kidney disease.Diabetes. 2017; 66: 791-800Crossref PubMed Scopus (169) Google Scholar For example, diabetes and hypoxia are associated with defective uptake, transcytosis, and/or lysosomal processing of filtered protein, alterations that partly contribute to microalbuminuria and the excretion of filtered low-molecular-weight proteins, such as L-FABP, NGAL, and γGT. The urinary excretion of KIM-1 is also increased owing to metalloprotease activity induced by proximal tubular stress, alongside increased intrarenal synthesis of KIM-1. The elevation of these urinary markers is associated with the degree of tubular injury, interstitial fibrosis, and inflammation in the diabetic kidney, as well as being linked to kidney prognosis.8Moresco R.N. Bochi G.V. Stein C.S. De Carvalho J.A.M. Cembranel B.M. Bollick Y.S. Urinary kidney injury molecule-1 in renal disease.Clin Chim Acta. 2018; 487: 15-21Crossref PubMed Scopus (48) Google Scholar In the long term, tubular hypertrophy, increased work, hypoxia, and subsequent remodeling is followed by progressive and cumulative senescence/apoptosis/atrophy of tubular epithelial cells.9Habib S.L. Kidney atrophy vs hypertrophy in diabetes: which cells are involved?.Cell Cycle. 2018; 17: 1683-1687Crossref PubMed Scopus (16) Google Scholar The high metabolic activity of senescent cells and their altered bioenergetic state further accelerates their decline (Fig 1). In advanced DKD, up to half of all glomeruli are attached to dilated and atrophic tubules, and up to 17% of glomeruli may be completely “atubular.”10Najafian B. Kim Y. Crosson J.T. Mauer M. Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: 908-917Crossref PubMed Scopus (99) Google Scholar These nonfunctioning nephrons are thought to result from atrophy at the critical junction between Bowman's capsule and the proximal tubule and likely represent the leading cause of nephron dropout and kidney function decline in DKD.10Najafian B. Kim Y. Crosson J.T. Mauer M. Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: 908-917Crossref PubMed Scopus (99) Google Scholar Protecting these vulnerable proximal tubular cells from hyperfiltration, oxidative stress, and hypoxia, therefore appears to be the best way to protect against kidney function decline and can currently be partly achieved combination therapy of both RAAS and SGLT2 inhibition. Directly blocking pathways that lead to tubular apoptosis may be effective for future management of DKD. For example, inhibition of apoptosis signal–regulated kinase, a critical signaling node that promotes apoptosis, has been associated with a slowing in GFR decline (NCT02177786), and a larger trial is ongoing (NCT04026165). The hemodynamic stress associated with hyperfiltration and the resulting release of trophic, inflammatory, and profibrogenic mediators is also implicated in the development and progression of ultrastructural changes in the glomerulus, including thickening of the glomerular basement membrane (GBM), mesangial expansion, podocyte remodeling, and glomerular hypertrophy. Early blockade of the RAAS slows progression of these ultrastructural changes by reducing intraglomerular pressure chiefly through its actions on the efferent arteriole.4Thomas M.C. Brownlee M. Susztak K. et al.Diabetic kidney disease.Nat Rev Dis Primers. 2015; 1: 15018Crossref PubMed Scopus (401) Google Scholar Although these benefits were not replicated in the RAAS trial,2Katavetin P. Katavetin P. Renal and retinal effects of enalapril and losartan in type 1 diabetes.N Engl J Med. 2009; 361 (author reply 1411): 1410-1411Crossref PubMed Scopus (9) Google Scholar the clear benefits of RAAS blockade in established DKD make them the first-line reno-protective therapy in all guidelines. It is possible to suggest that, like a dam, when the wall is breached, the loss the integrity of filtration barrier creates a vulnerability, which can be expanded by increased pressure and substantially attenuated by reducing it, with agents such as RAAS blockers and SGLT2 inhibitors. In almost all patients with diabetes, chronic hyperglycemia leads to progressive homogenous thickening of the GBM, largely attributable to expansion of its central lamina densa. Although many tubular changes occur early (see above), isolated GBM thickening is generally regarded as the first stage of DKD (class I). The greatest thickening of the GBM is observed in those individuals with incipient or overt nephropathy,11Dalla Vestra M. Saller A. Bortoloso E. Mauer M. Fioretto P. Structural involvement in type 1 and type 2 diabetic nephropathy.Diabetes Metab. 2000; 26: 8-14PubMed Google Scholar although even intermittent hyperglycemia associated with prediabetes appears to suffice to trigger GBM thickening. GBM width also correlates with the future risk of developing albuminuria and impaired kidney function in diabetes.4Thomas M.C. Brownlee M. Susztak K. et al.Diabetic kidney disease.Nat Rev Dis Primers. 2015; 1: 15018Crossref PubMed Scopus (401) Google Scholar As the GBM is predominantly assembled and turned over by podocytes, GBM thickening is most likely an adaptive (and ultimately maladaptive) response to increased mechanical and metabolic stresses, as well as altered connections/signaling after podocyte remodeling.12Marshall C.B. Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic?.Am J Physiol Ren Physiol. 2016; 311: F831-F843Crossref PubMed Scopus (66) Google Scholar As such, GBM thickening may be considered an early marker of “podocyte dysfunction” in diabetes, and thus therapies targeting podocytes (see below) the best way to modulate this increase. Conversely, the composition and properties of the GBM also influences podocyte differentiation and attachment. Changes in the composition of the GBM, including the loss of negatively charged proteoglycans, do not appear to directly mediate albuminuria in diabetes, although the resulting stiffening of the GBM also potentially impacts on intraglomerular hemodynamics.13Lewko B. Stepinski J. Hyperglycemia and mechanical stress: targeting the renal podocyte.J Cell Physiol. 2009; 221: 288-295Crossref PubMed Scopus (68) Google Scholar Widening of the subendothelial space is also observed in advanced DKD. This can give the appearance of a double-contour GBM or TBM and is sometimes called splitting or duplication, although is distinct from the lesion observed in mesangiocapillary GN. Widening of the subendothelial space is also seen in experimental models of endothelial dysfunction, reflecting its exudative origin. Like GBM thickening, this sign has also been shown to be prognostically important in patients with DKD. DKD is associated with significant podocyte injury, remodeling, dysfunction, and ultimately podocyte loss. This podocytopathy is observed early in the natural history of DKD and contributes significantly to the development and progression of albuminuria, glomerulosclerosis, nephron dropout, and subsequent impaired kidney function.14Ziyadeh F.N. Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy.Curr Diabetes Rev. 2008; 4: 39-45Crossref PubMed Scopus (320) Google Scholar, 15Wolf G. Chen S. Ziyadeh F.N. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy.Diabetes. 2005; 54: 1626-1634Crossref PubMed Scopus (508) Google Scholar, 16Li J.J. Kwak S.J. Jung D.S. et al.Podocyte biology in diabetic nephropathy.Kidney Int Suppl. 2007; : S36-S42Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar One early ultrastructural sign is the effacement of podocyte foot processes owing to retraction, widening, and shortening with the rearrangement of the podocyte actin cytoskeleton, creating the appearance of flattening on electron microscopy. This is associated with reduction in GBM anchors, reorganization of filtration slit pores, and the assembly of slit diaphragm proteins including nephrin, podocin and CD2AP. The loss of the highly specialized podocyte morphology may be considered as “dedifferentiation” or “simplification” in response to “podocyte stress,” and is observed in other glomerular disorders, including minimal change disease, membranous nephropathy, and HIV nephropathy. In the short term, podocyte dedifferentiation may conserve energy, facilitate mobility, survival, and even reentry into the cell cycle.17Herman-Edelstein M. Thomas M.C. Thallas-Bonke V. Saleem M. Cooper M.E. Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-beta: a model for diabetic podocytopathy.Diabetes. 2011; 60: 1779-1788Crossref PubMed Scopus (102) Google Scholar However, stressed and dedifferentiated podocytes also acquire a number of dysfunctional profibrotic, proinflammatory, and proliferative features17Herman-Edelstein M. Thomas M.C. Thallas-Bonke V. Saleem M. Cooper M.E. Kantharidis P. Dedifferentiation of immortalized human podocytes in response to transforming growth factor-beta: a model for diabetic podocytopathy.Diabetes. 2011; 60: 1779-1788Crossref PubMed Scopus (102) Google Scholar that trigger compensatory mesangial proliferation, capillary distension, and GBM thickening.4Thomas M.C. Brownlee M. Susztak K. et al.Diabetic kidney disease.Nat Rev Dis Primers. 2015; 1: 15018Crossref PubMed Scopus (401) Google Scholar Subsequent apoptosis, autophagy and detachment reduce podocyte density, potentially exposing the GBM, leading to synechiae and focal glomerulosclerosis. The importance of podocyte injury to diabetic kidney disease is demonstrated by the observations in experimental models that a podocyte-specific injury can recapitulate the structural changes of diabetic glomeruli.18Coward R. Fornoni A. Insulin signaling: implications for podocyte biology in diabetic kidney disease.Curr Opin Nephrol Hypertens. 2015; 24: 104-110Crossref PubMed Scopus (48) Google Scholar Similarly, podocyte-specific deletion of the insulin receptor results in significant albuminuria, together with histological features that recapitulate diabetic nephropathy but in a normoglycemic environment. At the same time, selectively protecting podocytes from hyperglycaemia with a podocyte-specific deletion of their glucose transporter (GLUT4)18Coward R. Fornoni A. Insulin signaling: implications for podocyte biology in diabetic kidney disease.Curr Opin Nephrol Hypertens. 2015; 24: 104-110Crossref PubMed Scopus (48) Google Scholar is able to prevent DKD without restoring normal levels of glucose. Taken together, these data support the rationale for renoprotective therapy glomerular podocytes. Certainly, blockade of the RAAS, endothelin-1 receptor blockade, and certain microRNA all have direct actions in podocytes. Exposure to hyperglycemia leads to an increase in glomerular size, known “glomerular hypertrophy.” This is largely owing to an increase in the fractional volume of the glomerulus occupied by the mesangium. This so-called “mesangial expansion” is initially caused by a modest and transient increase in mesangial cell size and numbers. However, subsequent expansion is almost entirely driven by the progressive increase in matrix components normally found in the mesangium, including fibrillar and nonfibrillar collagens, laminin, and fibronectin, as a result of increased matrix synthesis and altered matrix protein turnover (Fig 2). In advanced DKD, ectopic mesangial deposition of collagen I and III also occurs, associated with intractable glomerulosclerosis. Mesangial expansion is observed in almost all patients with DKD, and the presence of diffuse glomerulosclerosis (expansion present in >25% of the mesangium) defines “class II” diabetic nephropathy on histology. There is a strong link between the degree of mesangial matrix expansion and the progression of DKD, including the decline in GFR.19Ponchiardi C. Mauer M. Najafian B. Temporal profile of diabetic nephropathy pathologic changes.Curr Diab Rep. 2013; 13: 592-599Crossref PubMed Scopus (41) Google Scholar Expansion of the mesangial volume into capillary loops directly results in a reduction in capillary filtration surface area, therein contributing to glomerular hypertension and reduced glomerular filtration.20Lemley K.V. Abdullah I. Myers B.D. et al.Evolution of incipient nephropathy in type 2 diabetes mellitus.Kidney Int. 2000; 58: 1228-1237Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar More advanced DKD (class III) may be associated with nodular glomerulosclerosis and the classical “Kimmelstiel-Wilson” lesion (Fig 3) that forms owing to focal degeneration of mesangial cells and matrix (mesangiolysis) and subsequent nodular reorganization.21Wada T. Shimizu M. Yokoyama H. et al.Nodular lesions and mesangiolysis in diabetic nephropathy.Clin Exp Nephrol. 2013; 17: 3-9Crossref PubMed Scopus (19) Google Scholar As with diffuse glomerular sclerosis, the presence and extent of nodular lesions and mesangiolysis is independently predictive of faster decline in kidney function in patients with diabetes. Although microaneurysms are a consistent early feature of retinopathy, mesangiolysis in advanced kidney disease can also lead to capillary ballooning and the development of microaneurysms that form in glomerular capillaries devoid of their mesangial support.22Moreno J.A. Gomez-Guerrero C. Mas S. et al.Targeting inflammation in diabetic nephropathy: a tale of hope.Expert Opin Investig Drugs. 2018; 27: 917-930Crossref PubMed Scopus (107) Google Scholar The “class IV” lesion denotes extensive glomerulosclerosis in more than 50% of glomeruli. Although this histological staging system is widely used and predicts ultimate progression to ESKD, recent studies have suggested it cannot predict which patients will rapidly lose kidney function subsequent to the biopsy.23Misra P.S. Szeto S.G. Krizova A. Gilbert R.E. Yuen D.A. Renal histology in diabetic nephropathy predicts progression to end-stage kidney disease but not the rate of renal function decline.BMC Nephrol. 2020; 21: 285Crossref PubMed Scopus (5) Google Scholar This is possibly because rapid loss of kidney function in diabetes may be more tubular than glomerular in origin (see above).10Najafian B. Kim Y. Crosson J.T. Mauer M. Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy.J Am Soc Nephrol. 2003; 14: 908-917Crossref PubMed Scopus (99) Google Scholar Hyperglycaemia is not the direct trigger for mesangial expansion, as upregulation of glucose transport into mesangial cells does not recapitulate a diabetic phenotype.24Weigert C. Brodbeck K. Brosius 3rd, F.C. et al.Evidence for a novel TGF-beta1-independent mechanism of fibronectin production in mesangial cells overexpressing glucose transporters.Diabetes. 2003; 52: 527-535Crossref PubMed Scopus (62) Google Scholar Rather, changes in the glomerular environment and cross talk from podocytes, endothelial, and inflammatory cells appears to be important for mesangial expansion, including the release of different trophic and fibrogenic factors that are potential therapeutic targets, including angiotensin II and endothelin. The unique vulnerability of endothelial cells to ambient hyperglycemia means that endothelial dysfunction is a common factor in all diabetic complications. Specifically, the inability of endothelial cells to downregulate their glucose transport in response to high glucose levels25Kaiser N. Sasson S. Feener E.P. et al.Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells.Diabetes. 1993; 42: 80-89Crossref PubMed Scopus (267) Google Scholar leads to an overwhelming flux of intracellular glucose, which triggers the generation of pathogenetic mediators that contribute to the development of diabetic complications. The highly specialized capillaries of the glomerulus are equally vulnerable, undergoing functional and structural alterations in diabetes that are best characterized as “endothelitis.” These changes include increased adhesion and extravasation of leukocytes, production of chemokines/cytokines, exudation of plasma, changes in the biosynthesis and maintenance of the endothelial glycocalyx, altered vasomotor tone and hemostasis, endothelial senescence and apoptosis, endothelial-to-mesenchymal transition, neoangiogenesis, and rarefaction/capillary dropout.26Thomas M.C. Iyngkaran P. Forensic interrogation of diabetic endothelitis in cardiovascular diseases and clinical translation in heart failure.World J Cardiol. 2020; 12: 409-418Crossref PubMed Scopus (2) Google Scholar In the diabetic tissues, there is often a reduction in microvascular density (known as rarefaction or capillary dropout). This phenomenon has been best described in the diabetic retina, where rarefaction and pericyte dropout is thought to be a key driver of tissue hypoxia and subsequent problematic neoangiogenesis. However, the density of the peritubular capillary networks is also markedly reduced in the diabetic kidney, contributing to hypoxia (Fig 1), impaired hemodynamic responses, as well as progressive functional decline.27Bohle A. Mackensen-Haen S. Wehrmann M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure.Kidney Blood Press Res. 1996; 19: 191-195Crossref PubMed Scopus (176) Google Scholar Rarefaction is thought to be initiated and driven by inflammatory changes that lead to an imbalance between inadequate angiogenesis/regeneration and augmented vascular destruction/regression owing to apoptosis and/or endothelial senescence.28Erusalimsky J.D. Vascular endothelial senescence: from mechanisms to pathophysiology.J Appl Physiol (1985). 2009; 106: 326-332Crossref PubMed Scopus (291) Google Scholar Elevated levels of endothelin-1 are one contributor to endothelial dysfunction in diabetes, and beyond their hemodynamic effects, endothelin receptor blockade may have useful actions against diabetic nephropathy.29Tuttle K.R. Cherney D.Z.I. Therapeutic transformation for diabetic kidney disease.Kidney Int. 2021; 99: 301-303Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Diabetes also characteristically leads to progressive “arteriolar hyalinosis” involving both the afferent and efferent arterioles. Arterial hyalinosis is also seen other disorders associated with endothelial dysfunction, including hypertension, calcineurin use, and aging, although hyalinosis tends to be confined to the afferent arteriole in these conditions. Arteriolar hyalinosis is generally viewed as an exudative lesion, as plasma proteins such as albumin and immunoglobulins leave the vascular lumen owing to increased endothelial hyperpermeability and hydrostatic pressures, to progressively infiltrate and replace the vascular wall with amorphous acellular deposits. However, increased matrix production by activated smooth muscle cells may also play a significant role. A number of kidney biopsy studies correlate the presence and severity of arterial hyalinosis with the risk of progressive decline in kidney function in patients with type diabetes, beyond albuminuria.30Eadon M.T. Schwantes-An T.H. Phillips C.L. et al.Kidney Histopathology and prediction of kidney failure: a Retrospective Cohort study.Am J kidney Dis : official J Natl Kidney Found. 2020; 76: 350-360Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Progressive hyalinosis is thought to alter vascular function and glomerular hemodynamics, as well as eventually result in narrowing of the vascular lumen compromising blood flow within the nephron. As klotho appears to play an important role in preventing hyalinosis as well as other kidney lesions in diabetes, studies are now exploring the potential for augmenting this pathway including administration of recombinant α-klotho.31Hu M.C. Shi M. Gillings N. et al.Recombinant alpha-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy.Kidney Int. 2017; 91: 1104-1114Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar As in diabetic retinopathy, neovascularization is also observed DKD. New vessels emerge particularly from the afferent arteriole at the vascular pole and anastomose to peritubular capillaries; essentially bypassing the glomerulus and efferent a