The proximal tubule in the pathophysiology of the diabetic kidney

Abstract

Diabetic nephropathy is a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved in the early changes of the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review focuses on the proximal tubule in the early diabetic kidney, particularly on its exposure and response to high glucose levels, albuminuria, and other factors in the diabetic glomerular filtrate, the hyperreabsorption of glucose, the unique molecular signature of the tubular growth phenotype, including aspects of senescence, and the resulting cellular and functional consequences. The latter includes the local release of proinflammatory chemokines and changes in proximal tubular salt and fluid reabsorption, which form the basis for the strong tubular control of glomerular filtration in the early diabetic kidney, including glomerular hyperfiltration and odd responses like the salt paradox. Importantly, these early proximal tubular changes can set the stage for oxidative stress, inflammation, hypoxia, and tubulointerstitial fibrosis, and thereby for the progression of diabetic renal disease.

Fig. 1.

Proximal tubular glucose transport in the normal and diabetic kidney. A: under euglycemic conditions ∼97% of filtered glucose is reabsorbed via SGLT2 primarily in the early segments of the proximal tubule. A significant capacity of SGLT1 to reabsorb glucose in later segments of the proximal tubule is unmasked by SGLT2 inhibition (∼40% of filtered glucose under normoglycemia; see numbers in parentheses); based on (155) and the assumption that apical tubular glucose uptake in the kidney is primarily mediated by SGLT2 and SGLT1. B: diabetes increases glucose delivery to both SGLT2 and SGLT1 expressing segments. Glucose transporters GLUT2 and GLUT1 mediate glucose transport across the basolateral membrane, but GLUT2 may also translocate to the apical membrane in diabetes. ANG II, serum and glucocorticoid inducible kinase SGK1, hepatocyte nuclear factor HNF-1α, and protein kinase C PKCβ1 promote glucose reabsorption in the diabetic kidney, whereas the induction of oxidative stress (ROS) can inhibit. Na⁺-glucose cotransport is electrogenic and luminal K⁺ channels serve to stabilize the membrane potential (e.g., KCNE1/KCNQ1 in late proximal tubule).

Fig. 2.

The unique early growth phenotype of the diabetic proximal tubule and potential links to progressive renal disease. Hyperglycemia triggers growth of the proximal tubule, including an early phase of hyperplasia that is followed by G1 cell cycle arrest and development of hypertrophy and a senescence-like phenotype. A conceptual framework links this growth phenotype to tubulointerstitial fibrosis and inflammation with the tubulointerstitial injury aggravating hypoxia and leading to renal failure. See text for further explanations. AGE, advanced glycation end product; RAGE, receptor for AGE; ECM, extracellular matrix; TSC, tuberous sclerosis complex. [Modified from (152).]

Fig. 3.

Primary increase in proximal tubular reabsorption and strong suppression by high NaCl intake in the early diabetic kidney. Absolute proximal fluid reabsorption is shown as a function of single nephron GFR. Single nephron GFR was manipulated by perfusing Henle's loop downstream of an obstructing wax block and activating TGF to characterize reabsorption up to the late proximal tubule at similar levels of single nephron GFR in control rats (CON) and diabetic rats (STZ) on normal vs. high-NaCl diet. *P < 0.05 comparing the influence of STZ or high NaCl. [Modified from (150).]

Fig. 4.

Manifestations of a strong proximal tubular control of glomerular filtration in the early diabetic kidney. A: glomerular hyperfiltration. Hyperglycemia causes a primary increase in proximal tubular NaCl reabsorption through enhanced Na⁺-glucose cotransport and tubular growth (1). Enhanced reabsorption reduces the tubuloglomerular feedback (TGF) signal at the macula densa ([Na,Cl,K]_MD) (2) and via the physiology of TGF increases single-nephron glomerular filtration rate (SNGFR) (4). Enhanced tubular reabsorption and growth also reduce the hydrostatic pressure in Bowman space (P_BOW) (3), which by increasing effective filtration pressure can also increase SNGFR. The resulting increase in SNGFR serves to partly restore the fluid and electrolyte load to the distal nephron. B and C: The salt paradox. The nondiabetic kidney (B) adjusts NaCl transport to dietary NaCl intake primarily downstream of the macula densa and, thus, [Na,Cl,K]_MD or SNGFR is not altered. In contrast, diabetes (C) renders the reabsorption in the proximal tubule very sensitive to dietary NaCl (1) with subsequent effects on the luminal TGF signal (2) and SNGFR (3). [Modified from (145).]

Fig. 5.

Mechanisms of proximal tubular and tubulointerstitial injury in the diabetic kidney. Illustrated is the influence of hyperglycemia, luminal factors (derived from glomerular filtration and tubular release), tubular transport work, and peritubular blood flow on the interaction of proximal tubular cells with fibroblasts and inflammatory cells. TGFβ, chemokines, and the complex interactions between advanced glycation end products (AGEs), hypoxia and oxidative stress play key roles in the development of diabetic tubulointerstitial injury. ECM, extracellular matrix; RAGE, receptor for AGE; ROS, reactive oxygen species; SOD, superoxide dismutase. See text for further details. [Modified from (152).]